Malignant gliomas are very aggressive cancers, displaying high rates of mortality (within months) and resistance to therapeutic interventions. Levels of tissue factor (TF) expression have been shown to correlate with the histological grade of malignancy and vascularity in a number of cancer types, including glioblastoma. Further, TF is overexpressed around the typical necrotic foci found in glioblastoma [20]. These regions are highly hypoxic and seem to play a key role in glioblastoma aggressiveness, presenting an increased production of VEGF, IL-8 and metalloproteases [21,22].
Ixolaris, a tick salivary 140 amino acid protein containing 10 cysteines and 2 Kunitz-like domains, binds to FXa or FX as a scaffold for inhibition of the TF/FVIIa complex, in which the FVIIa catalytic site is inactivated. In contrast to TFPI, however, Ixolaris does not bind to the active site cleft of FXa. Instead, complex formation is mediated by the FXa heparin-binding exosite [26]. In addition, Ixolaris interacts with zymogen FX through a precursor state of the heparin-binding exosite [27]. Because Ixolaris displays potent and long-lasting antithrombotic activity this molecule might interfere with glioblastoma progression.
Inhibition or targeting of TF may therefore provide an anti-tumor strategy that could affect the survival of TF overexpressing tumor cells by inhibiting TF mediated cellular signaling or other activities. Further, this approach may prevent tumor growth indirectly via an antiangiogenic mechanism by inhibiting the growth or function of TF expressing intra-tumoral endothelial cells.
The present invention is directed to novel therapies for TF mediated or associated diseases or processes, and in particular cancer and vascular diseases.